Malaria is an infection caused by malaria parasites transmitted by Anopheles, and is an infection most feared by human beings since recorded history particularly in tropical and semitropical regions. The number of infected people once decreased by specific medicines such as quinine and chloroquine; however, drug-resistant parasites began to be discovered in the late 1950s and it is said that 3 to 5 hundreds of millions of people are still annually infected with the reemerging infectious disease and people totaling between 1 and 2 million die thereof. Although many other infectious diseases are treated or prevented with vaccines, for example, smallpox has been completely eradicated thereby, it is said that for malaria it would be essentially difficult to develop a vaccine since even a clue to develop the vaccine is not found despite that many researches have been conducted, probably because it is an infectious disease caused by parasites and has a complex life cycle.
Many researches are also conducted on the development of new drugs and the mechanism of drug resistance; however, a sense of crisis is expressed because more parasites having acquired drug resistance are found. Existing antimalarial drugs generally have strong side effects and cannot be prophylactically used in infested areas. The development of a new drug also poses a big economic problem since it is extremely expensive.
In 2005, Awa et al. discovered “Alaremycin” which was an antibiotic substance with a new structure found to have an antibacterial activity against Escherichia coli from a culture medium in which Streptomyces sp. strain A012304 grows by screening using the release of anucleate cells resulting from the inhibition of chromosome partitioning as a detection index (Non-patent Document 1) and was represented by formula (A) below:
(Non-patent Document 2).
Alaremycin was demonstrated to act as an inhibitor of porphobilinogen synthase (PBGS) as a porphyrin/heme biosynthesis system enzyme synthesizing porphobilinogen (PBG) by use of 5-aminolevulinic acid (5-ALA) as a substrate (Non-patent Document 3). PBGS is divided into two types based on a difference in a metal ion serving as a cofactor: one is a Zn2+ type distributed in cells of human and other animals and many bacteria and the other is a Mg2− type distributed in plant cells and some bacteria such as Pseudomonas aeruginosa (Non-patent Documents 4, 5, and 6).
PBGS is involved in the synthesis of porphyrin and its related compounds indispensable for the survival of living organisms, and its inhibitor, Alaremycin, has antibacterial activities against not only Escherichia coli used for the screening of producing bacteria but also Pseudomonas aeruginosa causing opportunistic infection in hospitals and problematical as a multiple-drug-resistant bacteria (Non-patent Document 3). The PBGS of Pseudomonas aeruginosa is PBGS of the Mg2+ type, which is different in the structure from that of humans; thus, PBGS of the Mg2+ type can probably be an effective target molecule in view of an antibacterial agent.
The acid amide (compound) of Alaremycin represented by formula (B) below is known as the anticancer antibiotic Primocarcin (Non-patent Document 7). The methyl ester (compound) of Alaremycin represented by formula (C) below is also known as a photosensitizer for the photo-dynamic therapy of cancer (Patent Document 1).

Heme proteins such as cytochrome c are present in the mitochondria of human malaria parasites as with humans, yeast and the like, and constitute an electron transport system; however, it is an established theory that the synthesis of ATP in parasites infecting, and proliferating in red blood cells approximately 100% depends on the extremely strong glycolytic system thereof and the involvement of mitochondria is almost negligible in terms of the ATP synthesis (Non-patent Document 7). However, it is known that malaria parasites have PBGS of the Mg2+ type and perform the de novo synthesis of heme despite surviving by ingesting a large amount of hemoglobin (Non-patent Documents 8 and 9).
However, the action mechanism of Atovaquone as an antimalarial agent already put to practical use as a pharmaceutical agent is to specifically inhibit a cytochrome bc1 complex (complex III) present in the mitochondrial membrane of human malaria parasites (Non-patent Document 10). This suggests that the electron transport system of mitochondria is essential for the proliferation of parasites.
The reason is unclear in many points why mitochondria necessitates the electron transport system despite the unnecessity of ATP synthesis; however, it is suggested that the system acts by transferring electrons released when dihydroorotic acid dehydrogenase as one of the enzymes in the pyrimidine synthesis system reduces dihydroorotic acid to make orotic acid, to cytochrome c oxidase via ubiquinone and cytochrome c (Non-patent Document 11). In addition, it is known that malaria parasites cannot utilize host-derived pyrimidine (Non-patent Document 12).